Probing initial transient oligomerization events facilitating Huntingtin fibril nucleation at atomic resolution by relaxation-based NMR
Abstract
Huntington's disease is a fatal neurodegenerative condition arising from polyglutamine expansion within the Huntingtin protein leading to fibril accumulation in neurons. The initial multimerization events occur on the submillisecond timescale and involve sparsely populated species that can be probed at atomic resolution by NMR. Using a minimalistic construct comprising the N-terminal amphiphilic domain and seven glutamines, we uncover a branched oligomerization pathway, one leading to a tetramer comprising a dimer of coiled-coil helical dimers, and the other resulting in a nonproductive, partially helical, dimer. The results illuminate the contribution of the N-terminal amphiphilic domain in prenucleation events that precede fibril formation.
- Publication:
-
Proceedings of the National Academy of Science
- Pub Date:
- February 2019
- DOI:
- 10.1073/pnas.1821216116
- Bibcode:
- 2019PNAS..116.3562K